The primary aim of this project is to increase our understanding of the role of the serotonergic neurotransmitter system in behavior. Animal model studies described in this project are often done in parallel with analogous neuropharmacologic and genetic studies of serotonergic neurotransmission in healthy humans and in patients with obsessive-compulsive disorder and other anxiety disorders as described in our other project report. In order to take advantage of transgenic technology, we have shifted from studies in rats to studies in mice. In the last year, the structure of the gene for the mouse serotonin transporter was elucidated, and the cellular localization and expression of the transporter in mouse brain was described. This year, we completed the initial characterization of the consequences of a 50% reduction (in +/- mice) and a complete lack (in -/- mice) of the mouse cell membrane serotonin transporter produced by disruption of the gene for this transporter via homologous recombination. Responses to two drugs of abuse, MDMA (3,4-methylenedioxymeth-amphetamine, "ecstasy") and cocaine, and to several other drugs were found to be gene- dose-dependently altered in these "knock-out" mice. Other drug responses were only altered in -/- mice; some of these reflected expected desensitization of serotonin receptor and post-receptor signaling mechanisms.